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H S Friedman

Publications and source records attributed to H S Friedman.

At least 145 records · Page 8Linked to original sources
PubMed1995

Psychosocial and behavioral predictors of longevity. The aging and death of the "termites".

Impulsive, undercontrolled personalities and major family stresses are known predictors of impaired adjustment, but long-term health effects are unclear. In an archival prospective cohort design, we followed up on L. M. Terman's (Terman & Oden, 1947) sample of gifted children by collecting and coding death certificates for the half of the sample that is now dead. Statistical survival analyses were used to predict longevity and cause of death as a function of parental divorce during childhood, unstable marriage patterns in adulthood, childhood personality, adult adjustment, and possible mediating health behaviors. Psychosocial factors emerged as important risks for premature mortality.

Adolescent↗
PubMed1995

Childhood conscientiousness and longevity: health behaviors and cause of death.

Previous research showed that conscientiousness (social dependability) in childhood predicted longevity in an archival prospective cohort study of bright children first studied by Terman in the 1920s (H. S. Friedman et al., 1993). Possible behavioral mechanisms for this robust association are now examined by gathering cause of death information and by considering the possible mediating influences of drinking alcohol, smoking, and overeating. Survival analyses (N = 1,215) suggest that the protective effect of conscientiousness is not primarily due to accident avoidance and cannot be mostly explained by abstinence from unhealthy substance intake. Conscientiousness may have more wide-ranging effects on health-relevant activities.

Adolescent↗
PubMed1995

An archival prospective study of mental health and longevity.

The relationship between mental health status and longevity was examined in an archival prospective cohort study (N = 1,103) derived from work begun by Lewis Terman in the 1920s. Degree of psychological maladjustment, cumulatively rated by Terman and his colleagues as of 1950, was found to be related to higher risk of all-cause mortality over a 4-decade follow-up period. The differences among causes of death were nonsignificant, but there was some indication that mental health problems were more strongly related to deaths from injury and cardiovascular disease. The overall relationship was significant for men but weaker for women. The effect was not substantially mediated by alcohol consumption, obesity, or cigarette smoking.

Adolescent↗
PubMed1995

Playing with pets and longevity among older people.

Models of the relations between contact with pets and better health are examined in an archival prospective study using data derived from the longitudinal study initiated by Terman in 1921 (current N = 343 men, 300 women). In survival analyses of documented longevity, playing with pets in 1977 (M age = 67 years) was not associated with mortality risk through 1991 for the total sample nor for those who were unmarried or those who were less satisfied with their human relationships. Playing with pets was not associated with health-prone attributes or healthy behaviors such as personality, social ties, education, and smoking.

Aged↗
PubMed1995

Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma.

Flunarizine, a diphenylpiperazine calcium channel blocker, is known to increase tumor blood flow. It also interferes with calmodulin function, repair of DNA damage and drug resistance associated with P-glycoprotein. Flunarizine was tested for its ability to modulate either cyclophosphamide- or melphalan-induced growth delay for a drug-resistant rhabdomyosarcoma xenograft (TE-671 MR) and the drug-sensitive parent line (TE-671), in which P-glycoprotein is not involved in the mechanism of drug resistance. Tumour blood flow was increased by 30% after a flunarizine dose of 4 mg kg-1, but no modification in growth delay was induced by melphalan (12 mg kg-1). In contrast, a 60 mg kg-1 dose of flunarizine had no effect on tumour blood flow, but the same dose created significant enhancement in melphalan-induced tumour regrowth delay in both tumour lines. The dose-modifying factor for flunarizine as an adjuvant to melphalan was approximately 2 for both tumour lines. Although blood flow measurements were not performed with the combination of flunarizine and melphalan, the results from flunarizine alone suggested that augmentation of melphalan cytotoxicity is not mediated by changes in blood flow. In contrast, flunarizine did not affect drug sensitivity to cyclophosphamide in groups of animals bearing the drug-sensitive parent tumour line. These results suggest that the mechanism of drug sensitivity modification by flunarizine is not related to modification of tumour blood flow, but may be mediated by modification of transport mechanisms that are differentially responsible for cellular uptake and retention of melphalan as compared with cyclophosphamide.

Animals↗
PubMed1995

Vasodilatory state of decompensated cirrhosis: relation to hepatic dysfunction, ascites, and vasoactive substances.

The objective of this study was to determine the relations between the hallmark circulatory finding of decompensated cirrhosis, a reduced systemic vascular resistance (SVR), and the indices of hepatic decompensation, the accumulation of ascites, and the concentrations of various vasoactive substances. At a university-affiliated teaching hospital, eighteen hospitalized patients with cirrhosis and 18 age- and sex-matched healthy subjects were used. This was a case-control study. Measurements included cardiac dimensions and indices derived from echocardiograms and Doppler studies, abdominal ultrasound estimates of ascites, indices of hepatic function, and various serum (S) and urinary (U) substances. Results showed that cirrhotics had increased left atrial and left ventricular dimensions, left ventricular mass, heart rate, cardiac output (CO), transvalvular velocities, and a decreased SVR. SVR was related to hepatic dysfunction, as reflected by an abnormal prothrombin time ratio (r = -0.64, p = 0.006), and also related to overall severity of liver disease as estimated by the Child-Pugh score (r = -0.53, p = 0.044). Although cirrhotics with ascites generally had a reduced SVR, estimates of ascites were directly related to SVR (r = 0.57, p = 0.03) and inversely related to CO (r = -0.53, p = 0.04). Concentrations of S and U digoxin-like immunoreactive substance (DLIS) were also increased, but the concentrations of S glucagon and estradiol were not elevated. The accumulations of S and U DLIS, S glucagon, and S estradiol were all related to hepatic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Prognostic value of contrast-enhanced magnetic resonance imaging in brainstem gliomas.

Brainstem gliomas are an important oncologic problem in the pediatric age group, constituting between 10 and 15% of childhood central nervous system neoplasms. A new classification scheme based on magnetic resonance imaging (MRI) has recently been proposed leading to speculation that gadolinium-DTPA-enhanced MRI may prove useful in defining the prognosis of subsets of patients with these tumors. We retrospectively reviewed gadolinium-DTPA-enhanced MRIs in 26 consecutive newly diagnosed pediatric patients (11 males, 15 females) from our institution between June 1988 and June 1994 with the diagnosis of diffuse brainstem glioma. The site, extent of invasion, T1 and T2 signals, and the pattern and the degree of contrast enhancement of the tumors were evaluated. We correlated the image features, clinical symptoms, and survival period in each patient. Seventeen tumors demonstrated contrast enhancement and 9 did not. The survival in the whole group ranged between 3 months and > 5 years with a median of 9 months. There was no statistical difference in the median survival between patients with or without contrast enhancement (11 versus 8 months).

Adolescent↗
PubMed1995

A pial window model for the intracranial study of human glioma microvascular function.

A new model for human brain tumor uses the intracranial placement of tumor xenografts under transparent glass cranial windows in nude rats, which require no immunosuppression for tumor engraftment. Adult male nude rats underwent implantation of human anaplastic astrocytomas (D-54 MG in 10 rats, D-317 MG in 11 rats). The tumors were placed on the pial surface of the left cerebral hemisphere under a glass cranial window overlying the cranium. Six control animals underwent cranial window placement alone. Tumor volumes were estimated from direct measurements of tumor dimensions, revealing a mean doubling time of 1.58 days for the D-54 MG tumors and 2.62 days for the D-317 MG tumors. When tumor volume estimates reached 35 mm3, photomicrographs revealed tumor vasculature in each tumor cell line that was distinct from both the other xenograft and the normal brain parenchyma. Qualitative differences in vascular appearance were supported by length/density coefficient calculations in each study group, with D-317 MG demonstrating the highest vascular density. Vessel caliber tended to be smaller in D-54 MG tumors than in D-317 MG tumors. Laser-Doppler measurements of local blood flow in tumors and normal parenchyma revealed significantly lower blood flow in both tumor cell lines than in control brain. Evaluation of leukocyte/endothelial cell interactions indicated more leukocyte rolling in D-54 MG tumors than in D-317 MG tumors; no evidence of this cell interaction was found in normal pial vasculature. This model allows direct serial inspection of human brain tumor growth and vascular function in an experimental animal and could be used to study tumor vascular and inflammatory responses to a variety of therapeutic manipulations.

Animals↗
PubMed1995

Sociodemographic and psychosocial factors in childhood as predictors of adult mortality.

OBJECTIVES: Childhood sociodemographic, psychosocial, and environmental factors are often assumed to affect adult health and longevity. These relationships were prospectively tested by using the 7-decade Terman Life Cycle Study of Children With High Ability (n = 1285). METHODS: Parental socioeconomic status, childhood health, objective childhood stressors (e.g., death or divorce of parents), and childhood personality were considered as potential predictors in hazard regression analyses of longevity through 1991. RESULTS: Parental divorce during childhood predicted decreased longevity, with sex controlled. Other potential social predictors failed to show significant associations with longevity. Three dimensions of childhood personality--conscientiousness, lack of cheerfulness, and permanency of mood (males only)--predicted increased longevity. The effects of parental divorce and childhood personality were largely independent and did not account for any of the gender difference in mortality. CONCLUSIONS: A small number of childhood factors significantly predicted mortality across the life span in this sample. Further research should focus on how these psychosocial factors influence longevity.

Aged↗
PubMed1995

MRI of papillary meningiomas in children.

We report two cases of papillary meningioma in children. The MRI appearance of this special type of meningioma is described for the first time. Both lesions were dura based and associated with cystic components. We review the literature pertaining to this type of meningioma and discuss the differential diagnosis of the MRI appearance. Because this is a malignant type of meningioma, early diagnosis and surgical intervention are important in the management of patients.

Child, Preschool↗
PubMed1995

Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene.

The type III deletion-mutant gene for the epidermal growth factor receptor (EGFRvIII) is frequently expressed in glioblastomas and in breast and non-small cell lung carcinomas. To understand its contribution to the malignant phenotype in humans, we transfected NR6 cells with the mammalian vector pH beta APr-1-neo containing cDNA for either EGFRvIII or wild-type EGFR. Western blot analyses showed that NR6 transfected with wild-type EGFR (NR6W) contained a normal-sized protein (170 kilodaltons); cells transfected with EGFRvIII (NR6M) contained a truncated protein (145 kilodaltons). NR6W cells demonstrated a saturation binding curve with 125I-labeled EGF (affinity, 1.8 x 10(8); r2 = 0.96). NR6M cells, however, showed a low but consistent level of 125I-labeled EGF binding (affinity, 4 x 10(7); r2 = 0.99) compared with NR6, which lacked binding. The population doubling time was shorter for NR6M (0.64 days) than for NR6W (1.1 days) and NR6V (2.27 days). Soft agar focus formation assay by NR6M was 4- to 5-fold higher than that by NR6W. In nude mice, NR6M (1 x 10(7) cells), without exogenous ligand, formed tumors within 12 days; no tumors were observed over 90 days in mice receiving identical doses of NR6W, NR6V, or NR6 cells. EGF stimulated autophosphorylation of receptor in NR6W (4- to 9-fold) but caused only slight (1.8- to 1.9-fold) to no enhancement in NR6M. Further, there was no difference in constitutive tyrosine kinase activity between NR6M and NR6W. Our results clearly indicate that EGFRvIII functions as an oncoprotein, but its intrinsic tyrosine kinase activity may not be responsible for its biological function.

3T3 Cells↗
PubMed1995

Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.

LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive monoclonal antibody B3 and a genetically engineered form of Pseudomonas exotoxin. Monoclonal antibody B3 reacts with a carbohydrate epitope that is found on a number of solid tumors (e.g., breast, ovarian, and lung carcinomas) that frequently invade the intrathecal space, causing neoplastic meningitis. The Pseudomonas exotoxin has been engineered to remove the binding domain to eliminate nonspecific binding. A model of human neoplastic meningitis using rats bearing the human epidermoid carcinoma A431 was used for therapeutic studies of immunotoxin LMB-1. Therapy was initiated 3 days after injection of the tumor cells, which was one third of the median survival time of untreated rats. A single intrathecal injection of 40 microgram increased median survival from 9 days with saline injection to 16 days (78%, P < 0.001), and a single dose of 200 microgram increased median survival to 25 days (188%, P < 0. 001). Three doses of 40 or 200 microgram given on days 3, 6, and 8 significantly increased the median survival of 9.5 days associated with saline injection to 40.5 days (326% increase) and 33.0 days (247% increase), respectively, with two long-term survivors (191-day survival) in each treatment group. LMB-1 had no therapeutic effect on the treatment of two B3 antigen-negative neoplastic meningitis models. Treatment of the antigen-positive A431 neoplastic meningitis with B3 alone or a nonspecific monoclonal, MOPC, coupled to the engineered Pseudomonas exotoxin produced no survival effects. Nontumor-bearing athymic rats showed no toxicity with a single dose of either 40 microgram or 200 microgram, or 3 doses of 40 microgram. However, when they were given three doses of 200 microgram, these rats showed weight loss and loss of neurological function, and two of eight animals died. These studies indicate that, in the range of the most therapeutically effective dosage, the immunotoxin LMB-1 is tolerated in the intrathecal space and should be considered for human intrathecal trials.

ADP Ribose Transferases↗
PubMed1994

Metabolism of O6-benzylguanine, an inactivator of O6-alkylguanine-DNA alkyltransferase.

O6-Benzylguanine effectively inactivates the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, leading to an increase in the therapeutic index of 1,3-bis(2-chloroethyl)-1-nitrosourea in nude mouse xenograft studies. To investigate the fate of this inactivator in mammalian systems, we examined its biodistribution and metabolism following i.p. administration of 8-[3H]-O6-benzylguanine to male Sprague-Dawley rats and BALB/c mice. Following administration to rats, there were significantly higher levels of radioactivity in liver than in lung, spleen, kidney, small intestine, and esophagus for up to 24 h. Major urinary metabolites were identified as O6-benzyl-7,8-dihydro-8-oxoguanine, N2-acetyl-O6-benzylguanine, and N2-acetyl-O6-benzyl-7,8-dihydro-8-oxoguanine. Debenzylated metabolites included guanine, 7,8-dihydro-8-oxoguanine, and N2-acetylguanine. In contrast to rat metabolism, acetylated derivatives were not found in mouse urine. However, O6-benzyl-7,8-dihydro-8-oxoguanine was a major metabolite in the mouse. O6-Benzyl-7,8-dihydro-8-oxoguanine was a very effective O6-alkylguanine-DNA alkyltransferase inactivator and exhibited a 50% effective dose in HT29 cell extracts of 0.3 microM compared to 0.2 microM for O6-benzylguanine. The O6-alkylguanine-DNA alkyltransferase depleting activity of N2-acetyl-O6-benzylguanine and N2-acetyl-O6-benzyl-7,8-dihydro-8-oxoguanine were, respectively, 120- and 325-fold lower than O6-benzylguanine in HT29 cell-free extracts.

Animals↗
PubMed1994

Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats.

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.

Animals↗
PubMed1994

Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan.

Previous investigations have revealed that the human TE-671 MR human rhabdomyosarcoma xenograft selected in vivo for melphalan resistance (M. C. Rosenberg, et al., Cancer Res., 49: 6917-6922, 1989) is cross-resistant to a wide variety of alkylating agents and to bleomycin, but is collaterally sensitive to etoposide. Although glutathione levels were noted to be elevated in TE-671 MR compared to the melphalan-sensitive parental TE-671 xenograft, treatment with buthionine sulfoximine to deplete glutathione levels did not fully restore melphalan sensitivity in the TE-671 MR xenograft. The present studies were undertaken to search for additional mechanisms of resistance in the TE-671 MR xenograft. Drug sensitivity testing performed at the dose of agents that was lethal to 10% of the animals revealed that the TE-671 MR xenograft maintained resistance to the bifunctional cross-linking agent 1,3-bis(2-chloroethyl)-1-nitrosourea and was cross-resistant to the topoisomerase I poison topotecan. Treatment with buthionine sulfoximine did not sensitize the TE-671 MR xenograft to 1,3-bis(2-chloroethyl)-1-nitrosourea. Further, even though O6-alkylguanine-DNA alkyltransferase levels were high in both the TE-671 and TE-671 MR xenografts, depletion of O6-alkylguanine-DNA alkyltransferase activity by treatment with O6-benzylguanine substantially sensitized the TE-671 xenografts but not the TE-671 MR xenografts, suggesting an additional mechanism of resistance. Measurement of additional enzyme activities that might be involved in DNA repair revealed significant elevations in DNA polymerase alpha (46 +/- 8 (SD) units/mg protein in TE-671, 69 +/- 6 units/mg protein in TE-671 MR, P < 0.05) and DNA polymerase beta (0.43 +/- 0.01 units/mg protein in TE-671, 0.78 +/- 0.12 units/mg protein in TE-671 MR, P < 0.05) but not DNA polymerase delta or total DNA ligase. Examination of topoisomerases by activity assays and Western blotting revealed a 2-fold increase in topoisomerase II and a 2-fold decrease in topoisomerase I in the TE-671 MR xenograft compared to the parental xenograft, apparently explaining the collateral sensitivity to etoposide and cross-resistance to topotecan. These results suggest that TE-671 MR xenografts contain multiple changes in activities of DNA repair-related proteins and other nuclear proteins that could contribute to alkylating agent resistance.

Alkyl and Aryl Transferases↗
PubMed1994

Alterations of the TP53 gene in human gliomas.

Glial tumors of all grades and histological types from 72 adults and 48 children were analyzed for mutations of the TP53 gene, loss of heterozygosity (LOH) for 17p, and accumulation of TP53 protein to determine whether the incidence and type of TP53 alterations differ among tumors of different histological type and between tumors from adults and children. These tumors were also evaluated for LOH for chromosome 10 and for amplification of the epidermal growth factor receptor, C-MYC, N-MYC, GLI, platelet-derived growth factor receptor-alpha, and murine double minute 2 genes to determine the patterns of molecular alterations involved in the progression of these neoplasms. Seventeen of the 120 tumors contained mutations of the TP53 gene. One of the tumors with TP53 gene mutation was from one of the 48 patients less than 18 years of age. Twelve of the 17 tumors with mutations occurred among the 27 patients in the 18-45-year age group, while 4 tumors with mutations were among the 45 patients more than 45 years old. There was also an increased incidence of TP53 mutation in patients with anaplastic astrocytoma histology. However, no significant association between presence of TP53 mutation and patient survival was observed. These studies demonstrate that TP53 gene mutations are a common mechanism for glial cell neoplasms in the 18-45-year age group but are unrelated to progression and advanced histological grade. LOH for chromosome 10 and gene amplification, however, occurring in 82 and 40%, respectively, of glioblastoma multiforme, whether seen alone or along with TP53 gene alterations, are related to advanced histological grade of the tumor. In childhood gliomas, in contrast, TP53 gene alterations, LOH for 17p and 10q, and gene amplification are uncommon in tumors of all grades, suggesting that presently unknown mechanisms are responsible for the genesis and progression of these tumors.

Adolescent↗